Antigen-processing cell-targeted conjugates
An anti-inflammatory conjugate including a polyamino acid backbone, a non-steroidal anti-inflammatory agent, and a moiety linking the anti-inflammatory agent to the backbone, wherein the polyamino acid backbone has a molecular weight greater than 250 kD.
Claims
1. An anti-inflammatory, non-immunogenic conjugate comprising:
- a polyamino acid backbone;
- a multiplicity of molecules of a non-steroidal anti-inflammatory agent; and
- a multiplicity of moieties linking said molecules to said backbone, wherein said polyamino acid backbone has an average molecular weight greater than 250 kD, said polyamino acid backbone comprises greater than 80 percent poly-.gamma.-glutamic acid, said moieties link said molecules of anti-inflammatory agent to said backbone via.alpha.-carboxylate groups of the poly-.gamma.-glutamic acid, and said conjugate is preferentially internalized by antigen-processing cells compared to said agent absent the backbone.
2. A conjugate of claim 1, wherein said anti-inflammatory agent is 15-deoxyspergualin, spergualin, piroxicam, or ibuprofen.
3. A conjugate of claim 1, wherein said moiety linking said anti-inflammatory agent to said backbone is an amide bond, an ester bond, or a thioester bond.
4. A conjugate of claim 1, wherein said polyamino acid backbone has a molecular weight between 500 kD and 1500 kD.
5. An anti-inflammatory, non-immunogenic conjugate comprising a derivatized polyamino acid of the formula:
- wherein each X.sup.m independently is C.sub.1-12 alkylene or deleted;
- each M.sup.m independently is (C.dbd.O)--O, (C.dbd.O)--NH, or (C.dbd.O )--S, wherein the carbon atom of M.sup.m is bonded either to X.sup.m or, when X.sup.m is deleted, to C.sup.*;
- each Y.sup.m independently is H, C.sub.1-12 alkyl, --(CH.sub.2).sub.a --O--(CH.sub.2).sub.b H, or a nonsteroidal anti-inflammatory agent, wherein at least one Y.sup.m is a nonsteroidal anti-inflammatory agent, and each of a and b independently is an integer between 0 and 12; and
- p is an integer between 1,900 and 15,000, m is an integer ranging between 1 and p; each n is independently an integer between 1 and 5; said polyamino acid backbone has molecular weight greater than 250 kD; and said conjugate is preferentiallv internalized by anti-processing cells compared to said agent absent the backbone.
6. A conjugate of claim 5, wherein each M.sup.m independently is (C.dbd.O)--O or (C.dbd.O)--NH.
7. A conjugate of claim 5, wherein Y.sup.m is 15-deoxyspergualin, spergualin, piroxicam, or ibuprofen.
8. A conjugate of claim 5, wherein n is 2.
9. A conjugate of claim 5, wherein X.sup.m is deleted.
10. A conjugate of claim 5, wherein the stereochemistry of each chiral carbon C.sup.* is L.
11. A conjugate of claim 5, wherein the stereochemistry of each chiral carbon C.sup.* is D.
12. A conjugate of claim 5, wherein p is between 4,000 and 13,000.
13. A conjugate of claim 5, wherein said polyamino acid backbone has a molecular weight between 500 kD and 1500 kD.
14. A method of treating an inflammatory disease in a mammal comprising administering to the mammal an effective amount of a conjugate of claim 1.
15. A method of claim 14, wherein said disease is rheumatoid arthritis, uveitis, psoriasis, type I diabetes, silicosis, polymyositis, coronary heart disease, pernicious anemia, pemphigus vulgaris, encephalitis, ulcerative colitis, Sjogren's syndrome, scleroderma, mixed connective tissue disease, systemic lupus erythematosus, or emphysema.
16. A method of targeting an anti-inflammatory agent to a circulating antigen-processing cell in a mammal, comprising
- obtaining an anti-inflammatory conjugate comprising a polyamino acid backbone, an anti-inflammatory agent, and a moiety linking said anti-inflammatory agent to said backbone, wherein said polyamino acid backbone has a molecular weight greater than 250 kD; and
- injecting an amount of said anti-inflammatory conjugate into the mammal, thereby delivering an effective amount of said anti-inflammatory agent to a circulating antigen-processing cell in the mammal.
17. A method of claim 16, wherein said polyamino acid backbone is a poly-.gamma.-glutamic acid backbone.
18. A method of targeting an anti-inflammatory agent to a circulating antigen-processing cell in a mammal, comprising
- obtaining an anti-inflammatory conjugate of claim 5; and
- injecting an amount of said anti-inflammatory conjugate into the mammal, thereby delivering an effective amount of said anti-inflammatory agent to a vascularly circulating antigen-processing cell in the mammal.
| 4151173 | April 24, 1979 | Vogel |
| 4349530 | September 14, 1982 | Royer |
| 4356166 | October 26, 1982 | Peterson et al. |
| 4386026 | May 31, 1983 | Ponpipom et al. |
| 5030834 | July 9, 1991 | Krumdieck et al. |
| 5118784 | June 2, 1992 | Kubota et al. |
| 5225182 | July 6, 1993 | Sharma |
| 0 094 844 | November 1983 | EPX |
| 0 485 158 | November 1991 | EPX |
| 0 485 157 | November 1991 | EPX |
| WO 87/03891 | July 1987 | WOX |
| WO 92/05802 | April 1992 | WOX |
| WO 92/19248 | November 1992 | WOX |
- De Marre, et al., "Evaluation of the hydrolytic and enzymatic stability of macromolecular Mitomyci C derivatives", Journal of Controlled Release, 31:89-97, (1994). Franssen, et al., "Hepatic and Intrahepatic Targeting . . . And Neoglycoproteins As Carrier Molecules", Biochemical Pharmacology, 45:1215-1226, (1993). Liso, et al., "Antinociceptive and antipyretic properties . . . controlled delivery system", Journal of Controlled Release, 33:429-436, (1994). Roos, et al., "Physicochemical and antitumor . . . of mitomycin C", International Journal of Pharmaceutics, 22:75-87, (1984). van Heeswijk, et al., "The Synthesis and Characterization of Polypeptide . . . with Adriamycin. Part 1", Journal of Controlled Release, 1:301-315, (1985). Anderson, "In Vitro and In Vivo Studies of Drug-Releasing Poly(amino acids)," Annals New York Academy of Sciences, 67-75 (1985). Borbely et al., "Biosynthesis and Chemical Modification of Poly( -glutamic acid)," Polymer Bulletin 32, 127-132 (1994). Goodman et al., "Immunochemical Studies on the Poly--D-glutamyl Capsule of Bacillus Anthracis. I. Characterization of the Polypeptide and of the Specificity of Its Reaction With Rabbit Antisera," Biochemistry 5, No. 2 657-664 (1966). Goodman et al., "Immunochemical Studies on the Poly--D-glutamyl Capsule of Bacillus Anthracis. III. The Activity with Rabbit Antisera of Peptides Derived from the Homologous Polypeptide," Biochemistry 7, No. 2 706-710 (1968). Jensen et al., "Production of Recombinant Human Growth Hormone in Escherichia coli: Expression of Different Precursors and Physiological Effects of Glucose, Acetate, and Salts," Biotechnology and Bioengineering, 36 1-11 (1990). Nitecki et al., "Immunochemical Studies on the Poly( -glutamyl Capsule of Bacillus anthracis. II. The Synthesis of Eight Dipeptides and Four Tripeptides of Glutamic Acid," Biochemistry 5, 665-672 (1966). Shah et al., "New Polymers Derived From Natural Origin -Poly(Glutamic Acid)," Polymer Preprints, 33 No. 2 488-490 (1992). Thorne et al., "Production of Glutamyl Polypeptide By Bacillus Subtilis," Journal of Bacteriology, 68 307-315 (1954). Tsukada et al., "An Anti-.alpha.-Fetoprotein Antibody-Daunorubicin Conjugate With A Novel Poly-L-glutamic Acid Derivative as Intermediate Drug Carrier," JNCI, 73, No. 3 721-729 (1984).
Type: Grant
Filed: Dec 19, 1997
Date of Patent: Apr 27, 1999
Inventors: Joel K. Swadesh (Worcester, MA), Martin Sevoian (North Amherst, MA)
Primary Examiner: Keith D. MacMillan
Law Firm: Fish & Richardson P.C.
Application Number: 8/994,334
International Classification: A61K 3119; A61K 3154;
